ABSTRACT Theoverallgoalofthisproposalistocomparevascularmarkersbetweenamnesticmildcognitiveimpairment(MCI) subjectswithamyloidorAlzheimer?sdisease(AD)pathology,andthenewlyidentifiedMCIsubjectswithsuspected non-amyloidpathology(SNAP-MCI).Theinnovationofthisworkisthatwewillexplorevascularpathologyandits roleasadriverofcognitivedeficitsinthisnewcohort.ComparedtotheamyloidpositiveMCIsubjects,SNAP-MCI subjectsshowsimilarneurodegeneration,similaramnesticsymptoms,butnormalamyloidaccumulationinthebrain. The higher burden of white matter hyperintensities in SNAP-MCI suggests vascular involvement in the disease mechanism.However,notmuchisknownregardingvascularabnormalitiesinthisgroup.Toaddressthisgap,we will compare cerebral blood flow (Aim 1) and cerebrovascular reserve (Aim 2) between cognitively normal older adults,amyloidpositiveMCIsubjects,andSNAP-MCIsubjectsfromtheUniversityofWashingtonADResearch Center(directedbyprimarymentor,Grabowski).Wewillthenrepeatthesemeasurementsafter18-24monthsto tracklongitudinalchanges(Aim3).Wewillassesstheco-localizationofthevascularandamyloidpathologiesusing amyloidpositronemissiontomography(PET,TrainingAim4).WehypothesizethatamyloidpositiveMCIsubjects will have the lowest cerebral blood flow and vascular reserve due to the dual effects of amyloid and neurodegeneration.Importantly,thepresenceofvascularpathologyinSNAP-MCIsubjectswillunderlinetheroleof a non-amyloid, vascular mechanism initiating dementia of Alzheimer type. We will apply arterial spin labeling magnetic resonance imaging (MRI) to estimate cerebral blood flow. We will use a breath-hold functional MRI paradigm,validatedinourlab,toevaluatecerebrovascularreserve.InasubsetofMCIsubjects,wewillperform dynamicPETimagingtodetermineR1,i.e.,PETmeasureofCBF,andcorrelateitwithourMRImeasureofCBF. WewillusethestaticFlorbetapir18FPETimagesforasemi-quantitativeregionalanalysisofamyloidaccumulation. Thesignificanceofthisworkisthatitwillenableustoidentifyvasculartargetsforearlyintervention.Ourfuturework willfocusonapplyingtauPETtodetermineneurodegenerationpatternsthatarespecifictoSNAP-MCIandtheir relationtovascularabnormalities.Candidate:Thelong-termgoalofthecandidateistobecomealeaderinAD imagingresearch.ThecandidatehasastrongtechnicalbackgroundinMRIphysics,dataprocessing,andanalyses. Shefirmlybelievesthatamulti-modalanalysisisthekeytobridgethesystems-levelMRImarkerswiththecellular levelPETmarkersforabetterunderstandingofADmechanisms.Tocomplementhertechnicalbackground,she willtakecoursesinneurology,allowinghertoformulateandtestwell-informedhypothesesfordegenerativedisease mechanisms.ShewillsecurenewskillsinstaticanddynamicPETanalyses,aswellasPET-MRIimagefusion.She hasprovidedadetailedplanforherresearchpublicationsandfirstR01submission.Thecandidate?smentorswill ensurethatsheiswell-preparedtolaunchherindependentcareerasanimagingresearchscientist.